The etiologic agent, such as human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), that causes acquired immunodeficiency syndrome (AIDS), encodes for a specific aspartyl proteinase (HIV-protease). The inhibition of HIV-proteases by peptidomimetic structures incorporating a hydroxyethylamine (HEA) isostere offers a promising approach for the treatment of AIDS.
Many potent drugs, such as amprenavir, fosamprenavir, saquinavir, darunavir, and palinavir which belong to the HEA class, have complex structures equipped with multiple stereogenic centers. Due to the potential biological importance of these HIV inhibitors, considerable effort has been directed at methods for their synthesis.
HIV protease inhibitors have been developed as some of the most promising chemotherapeutic agents for the treatment of AIDS, and they exhibit complex structures equipped with multiple steriogenic centers. Thus, synthetic organic chemists have been attracted towards development of an efficient and practical synthetic route for these inhibitors. Amprenavir 1 developed by Vertex and GlaxoSmithKline, is an HIV protease inhibitor that was approved by the FDA in 1999. Fosamprenavir 2, launched in 2003, is a prodrug with increased therapeutic efficacy.
Several publications have disclosed the synthesis of HIV protease inhibitors, and some relevant documents are mentioned below.
WO 2000/018384 discloses a pharmaceutical combination comprising (S)-2-ethyl-7-fluoro-3oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester or a physiologically functional derivative thereof and 4 amino 4-amino-N-((2-syn,3S)-2-hydroxy-4-phenyl-3((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzenesulfonamide (amprenavir) or a physiologically functional derivative thereof.
U.S. Pat. No. 6,436,989 discloses fosamprenavir calcium and other salts of fosamprenavir, such as sodium, potassium, and magnesium, their pharmaceutical compositions, and methods of treating HIV infection and inhibiting aspartyl protease activity in a mammal. U.S. Pat. No. 6,514,953 discloses polymorphic Form I of fosamprenavir calcium, its pharmaceutical composition, and its method of use for treatment of an HIV infection, wherein the process for the preparation of a fosamprenavir or its salts comprises reacting a compound of formula (II) with a phosphorylating agent and further reduction.
Further preparation of saquinavir is described in U.S. Pat. No. 5,196,438 and also European Patent No. EP432695, wherein (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was hydrogenated with hydrogen gas at higher pressure in presence of Rhodium on carbon as catalyst using 90% acetic acid. The final step involves treatment of (2S)—N-[(1S,2R)-3-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-octahydro-1H-isoquinolin-2-yl]-1-benzyl-2-hydroxy-propyl]-2-amino-butanediamide with quinaldic acid in presence of hydroxybenzotriazole and dicyclohexylcarbodiimide using N-ethylmorpholine as base.
Also, the preparation of darunavir is reported in WO 99/67417 and WO 99/67254.
The multistep stereoselective synthesis of palinavir, a potent HIV protease inhibitor, is disclosed in J. Org. Chem., 1997, 62 (11), pp 3440-3448 by Pierre L. Beaulieu et al.
Although several methods have been tried for the syntheses of HIV protease inhibitors, some of them require chiral auxiliaries or use of chiral building blocks and exotic reagents, involve longer reaction sequences, and expensive catalysts coupled with low enantiomeric excess, making the processes non feasible industrially.
Additionally, several synthetic approaches of azido epoxide (5), the key chiral building block in the synthesis of HEA-based HIV protease inhibitors, have been reported in the literature.
An article titled “Efficient Synthesis of 2(S)-[1(S)-Azido-2-phenylethyl]oxirane” by Sangwoo Park, Sangmi Lee, and Ho-Jung Kang in Bull. Korean Chem. Soc. 2008, Vol. 29, No. 5 1073, discloses efficient synthesis of 2(S)-[1(S)-azido-2-phenylethyl]oxirane (1) from acetonide 2 as a starting material by 9 steps with two purification steps at alcohol 3 and oxirane 1, respectively, in overall yield of 48%, providing an expedient route to the facile, practical, and large-scale production of the desired epoxide 1 and other related structural motiffs from the cheaper D-isoascorbic acid.
WO 99/67254 provides a retroviral protease-inhibiting compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, or an ester thereof, wherein A is a group of formula (II), (III), (IV), or (V);

The said patent application further provides a method of synthesizing the multidrug-resistant, retroviral protease-inhibiting compounds, such as for example, ritonavir, saquinavir, indinavir, amprenavir, AZT, ddl, ddC, d4T, 3TC, ABV (abacavir), DLV (delaviridine), and PFA (foscarnet), of the present invention.
The said synthesis method is generally illustrated in FIG. 4 of WO 99/67254, wherein a compound of Formula (I) is synthesized in several steps starting from azidoepoxide (i), amine (ii) is nucleophilically added to azidoepoxide (i) to afford aminoalcohol (iii), which is then reacted with intermediate (iv), which can be displaced by the amine of aminoalcohol (iii), to provide azide (v); reduction of azide (v), provides intermediate (vi), which is subsequently coupled with activated bicyclic ligand (vii) gives compound (I)(c.f. below scheme).

However, the few methods that relate to the synthesis of the azido epoxide compound suffer from limitations, such as the use of chiral building blocks, introduction of chirality in the early stages, long reaction sequences, the use of expensive catalysts, low % ee, and so on, and hence are not amenable for scale-up studies.
Therefore, there is a need in the art to provide an efficient method of synthesizing azido epoxide compound (5), which can be further used to provide an efficient synthetic method for the preparation of HIV protease inhibitors, such as amprenavir, fosamprenavir, saquinavir, darunavir, palinavir, and their structural analogues, that proceed with high enantioselectivities (99% ee), in a concise manner.
Accordingly, the present invention provides a new synthetic route for the preparation of racemic azido epoxide (5) from commercially available allylic alcohol.
Accordingly, the present inventors have further developed a new synthetic route for the preparation of HIV protease inhibitors, comprising hydrolytic kinetic resolution (HKR) of a racemic azido epoxide as a key step to obtain the HIV protease inhibitors in high yield and high enantioselectivity. Further, the process developed by the inventor is efficient, cost effective as it involves simple organic reagents and water, and industrially viable, as well as socially important.